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From Signal Diversity to Cellular Identity – How Complex Ca2+ Transients Shape the Fate of Oligodendrocyte Lineage Cells
Oligodendrocyte lineage cells (OLCs) are key contributors to the development and maintenance of healthy neural circuits in the brain. They begin their life as oligodendrocyte precursor cells (OPCs), which form synapses with neurons and actively monitor their activity, before transforming into premyelinating oligodendrocytes (pmOLs) and eventually mature oligodendrocytes (OLs), the cells responsible for myelination in the central nervous system (CNS). Crucially, OLCs maintain the ability to proliferate and generate new OLs throughout adulthood, a process that is essential to sustain adaptive myelination and myelin repair. While the proper development of OLCs is vital to the overall function of brain circuits, little is known to date about the specific mechanisms that govern their evolution, including if and how neuronal activity dictates their fate and survival. In this study, I explore the role of Ca2+, an all-important second messenger, across the entire oligodendrocyte lineage and investigate its impact on OLCs at both the cellular and population level. Using state-of-the art multiphoton microscopy and novel transgenic mouse lines, I performed chronic Ca2+ imaging of OLCs in the cortex of awake “freely-moving” mice to simultaneously monitor intracellular Ca2+ dynamics and lineage progression. I found that OLCs produce Ca2+ transients that vary substantially both spatially (ranging from micrometer-size Ca2+ microdomains to branch-wide and somatic events) and temporally (ranging from hundreds of milliseconds to over 10 seconds) and that they exhibit distinct Ca2+ signatures depending on their maturity level as well as on the arousal state of the animal itself. In addition, I discovered that norepinephrine (NE), which is released as mice engage in exploratory behavior, significantly impacts OLC Ca2+ dynamics and promotes their differentiation into mature OLs. I also show that these mature OLs are capable of transducing mechanical stimuli into Ca2+ signals, which could play a role in the remodelling and fine tuning of myelin sheaths. Overall, this study demonstrates that Ca2+ plays a central role in OLC physiology throughout their evolution, allowing them to integrate all matters of extracellular cues to modulate their behavior and optimize their function both at the cellular and population level.
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500 Naturwissenschaften und Mathematik
500 Natural sciences and mathematics
570 Biowissenschaften, Biologie
570 Life sciences